Development of the kidney is a process involving branching morphogenesis. The metanephros, or permanent kidney, is first observed at E10.5 in the mouse. Reciprocal inductive interactions between the ureteric bud (UB), an outgrowth of the Wolffian duct, and the metanephric mesenchyme (MM) result in branching of the UB to form the collecting duct system of the mature kidney and the differentiation of the mesenchyme into the glomeruli and uriniferous tubules (Saxen, 1987, Organogenesis of the kidney. Cambridge University Press., Cambridge). In both embryonic and adult kidney, most epithelial structures are surrounded by renal interstitium. Interstitial cells are responsible for the production of extracellular matrix components and development and support of the functional units of the kidney, including feedback control of the glomerular capillary blood flow.
The adult (Hume et al., 1983, J Exp Med., 158 1522-36) and embryonic mammalian renal interstitium contains resident macrophages. The phenotype and potential tissue specific function of renal macrophages, and tissue macrophages in general, is not well defined. A little is known about their growth factor production and receptor profile. The expression of Cxcr4 on renal macrophages allows them to respond to the production of Cxcl12 by the comma and S-shaped bodies of the kidney (Grone et al., 2002, JASN, 13, 957-67). Conversely, renal macrophages express Cxcl10 (IP-IO), allowing them to signal to the Cxcr3 receptor in the developing kidney mesenchyme (Grone, et al., 2002, supra).
The importance of macrophage infiltration in development is mirrored in adult tissue repair. In numerous examples of tissue repair, including models of acute damage to muscle, liver, lung, gastrointestinal tract and peripheral nervous system, infiltration by macrophages and production of macrophage-derived trophic factors appears to be absolutely essential for regeneration (Kluth, et al., 2004, Kidney International., 66 542-57).
But macrophages are the classical two-edged sword.
In systems where the damage is severe or progressive and where the damage stimulus remains, including chronic inflammation, macrophages are the dominant cell type in the inflammatory exudates and they are implicated directly in cell death and tissue damage. Indeed, conventional wisdom in both renal disease and allograft rejection has been that macrophages are responsible for damage (Eitner, et al., 1998, Transplantation, 66, 1551-7; Segerer, et al., 2003, Curr. Opin. Nephrol. Hypertens., 12, 243-9) and many therapeutic strategies have focused on ways in which to reduce macrophage recruitment and activation. A reduction in the production of chemokines involved in macrophage recruitment, proliferation and activation has been shown to be potentially beneficial not only in renal disease classically associated with immune perturbations, such as glomerulonephritis and lupus nephropathy, but also in unilateral ureteric obstruction and diabetes (Naito, et al., 1996, Mol. Med., 2, 297-312; Utsunomiya, et al., 1995, J. Diabetes Complications, 9, 292-5). However, this is not always the case (Veilhauer, et al., 2004, Kidney Blood Press. Res., 27, 226-38; Holdsworth, et al., 2000, Curr. Opin Neprhol. Hypertens., 9, 505-11). Macrophage migration inhibitory factor (MIF), while associated with renal injury in the rat, has been shown to be independent of macrophage recruitment and renal fibrosis in a unilateral ureteral obstruction (UUO) model in the mouse (Rice et al., 2004, Nephrology 9 278-287).
CSF-1 (macrophage colony-stimulating factor; M-CSF) is the major growth factor for cells of the macrophage lineage. Increased CSF1 levels are associated with renal disease and allograft rejection (Isbel, et al., 2001, Nephrol. Dial. Transplant., 16, 1638-47; Le Muer, et al., 2002, Leukoc. Biol., 72, 530-7; Le Muer, et al., 2004, Nephrol. Dial. Transplant., 19, 1862-5). CSF-1 acts on its target cells by binding to colony-stimulating factor 1 receptor (CSF-1R), a cell-surface tyrosine kinase receptor encoded by the c-fins proto-oncogene, which is expressed in macrophage and trophoblast cell lineages (Sasmono, et al., 2003, Blood, 101, 1155-1163). c-fms is critical for the proliferation, survival and differentiation of macrophages as disruption of the gene results in large depletions of macrophages in most tissues (Dai et al., 2002, Blood, 99, 111-20).
Mutation of the CSF-1 gene, such as that present in op/op mice, or blockade of CSF-1 function with either anti-CSF-1 or anti-c-fms antibodies, greatly reduces renal damage in several models including experimental glomerular nephritis, renal tubular interstitial nephritis, autoimmune nephritis and ureteral ligation (Lenda, et al., 2003, J. Immunology, 170, 3254-62; Jose, et al., 2003, Am. J. Transplant, 3, 294-300). In each of these model systems, CSF-1 is produced locally, and probably also systemically (although this is seldom measured), and the interpretation has been that CSF-1 acts to recruit and activate macrophages to cause tissue damage.
Administered granulocyte colony stimulating factor (G-CSF) has been shown to protect mouse kidneys from subsequent cisplatin damage. Cisplatin is a widely-used anticancer drug that can induce acute renal failure due to renal tubular injury. The protective effect provided by G-CSF was enhanced by CSF-1 (i.e., M-CSF; Iwasaki, et al., 2005, JASN, 16, 658). However, the administration of CSF-1 alone prior to the induction of cisplatin damage showed no protective effect.
CSF-1 has been reported to impair the progression of lipid-induced nephrotoxiocity in streptozotocin-induced diabetic rats, by modulating the recruitment of macrophages to the glomerulus (Utsunomiya, et al., 1995, supra). However, this contradicts Miyazaki, et al., 1997, Clin. Exp. Immunol., 108, 318, who showed that increased M-CSF production is associated with an increase in recruitment of macrophages to the glomerulus in lipid-induced nephrotoxicity.
In humans, renal disease is a severe and debilitating ailment that is broadly classified as “chronic” or “acute”.
Chronic renal disease (CRD) refers to the gradual decline in renal function. This ultimately progresses to end stage renal disease (ESRD) when the renal filtration rate falls below 10%. CRD prevalence is rising at 6-8% per annum worldwide. Subsequently the incidence of ESRD is also increasing. Currently, the only available treatment options for ESRD are renal transplantation and dialysis. Transplantation extends survival over dialysis, but is associated with surgical morbidity and faces a shortage of viable organs. Dialysis replaces solute clearance but does not replace all renal functions, such as endocrine or metabolic functions. For those receiving dialysis treatment, the quality of life is poor and mortality rates are high (16% pa). Acute renal failure (ARF) is a common outcome in the postoperative patient, due to nephrotoxic or ischaemic insult during treatment for another condition. ARP patients receive dialysis treatment, but the lack of adjunct therapy to dialysis is thought to contribute to the high mortality rate of 50-75%. For both acute and chronic renal conditions, there is an urgent need for more advanced therapeutic approaches.
Compared to infants who have born following a normal, full term pregnancy, premature infants, particularly babies born before 32 weeks of gestation, are at a considerably greater risk of developing a number of serious health problems including, for example, renal and lung disorders.
For instance, the low birth weight and insufficient physical development of premature infants predisposes them to respiratory complications such as respiratory distress syndrome (RDS) and chronic lung disease (also known as bronchopulmonary dysplasia). RDS is associated with irregular breathing difficulties and occurs in approximately 60 to 80 percent of infants born before 28 weeks gestation, and in 15 to 30 percent of those born between 32 and 36 weeks of gestation. Treatment of such infants typically involves supplemental oxygen, but in some cases, also requires the use of a mechanical ventilator and continuous positive airway pressure. Moreover, in severe cases, treatment will additionally involve the administration of an artificial lung surfactant. While such treatments are very successful, long-term ventilator treatment is undesirable since this can lead to lung deterioration, which in turn, can lead to bronchopulmonary dysplasia.
It is also known that premature infants are born with reduced numbers of nephrons (filtration units of the kidney), an outcome that may be associated with increased risk of developing hypertension and reduced renal function following injury later in life.
Lung Development: Analogies Between Human and Mouse:
The human lung is derived from the foregut at about 4 weeks gestation and begins as a diverticulum. The lung diverticulum is covered with splanchnic mesoderm that gives rise to the tissue components of the mature adult lung such as cartilage, smooth muscle and blood vessels. Lung development is characterised by branching morphogenesis that gives rise to the primary, secondary and tertiary bronchi. The stages of foetal lung development are classified into three distinct phases, namely; the pseudoglandular, canalicular and saccular phases. Some aspects of alveolar lung development including epithelial cell differentiation begin in the canalicular phase. However, approximately 15-18% of alveoli form late in gestation, with most of the alveoli formed after birth. Shortly after birth, the surface area of the air-blood interface increases with the formation of the alveolar ducts and sacs.
Premature infants can survive with lung development in the late canalicular or early saccular phase. This is a phase when the conducting airways have stopped branching and are enlarging at their distal termini. There is a progressive loss of extracellular matrix and mesenchymal cells that separate the capillaries from the sites of alveoli. These premature infants survive without alveoli by treatment involving mechanical ventilation and the administration of an artificial lung surfactant, although, as mentioned above, they are at risk of developing bronchopulmonary dysplasia.
In mice, the lung also arises from the ventral foregut, but at approximately embryonic day 9.5 (E9.5). Subsequently, the respiratory tree develops through the pseudoglandular (E9.5-16.5), canalicular (E16.5-17.5), and saccular (E17.5-postnatal day 5) phase. While mouse and human lung development is highly analogous from an embryological point of view and while the same genes are critical in both organisms, in contrast to the human lung, alveolarisation is not complete before birth in the mouse. At birth, the mouse lungs consists of immature terminal saccules with some secondary septa, with alveolarisation and alveolar separation occurring during the during the first 1-3 postnatal weeks. The alveolar surfaces increase through the enlargement of pre-existing alveoli with formation of new alveoli.
Kidney Development: Analogies Between Humans and Mice:
The development of the kidney is highly analogous between human and mouse with respect to the embryo logical origin of the tissues involved, the morphogenetic processes and the genes regulating these processes.
In the human (as for the mouse), both the renal and genital systems originate from the intermediate mesoderm. Development of the kidney undergoes three distinct stages before resulting in the mature adult kidney. The process begins with the formation of the pronephros, then the mesonephros and finally the metanephros, after which the pronephros and mesonephros regress, and the metanephros remains to form the functional adult kidney. Metanephric development begins with the outgrowth of ureteric bud, originating from the Wollfian duct, invading the surrounding metanephric mesenchyme. The functional units within the kidney responsible for filtration of the blood, concentration of the filtrate to form urine and reclamation of water and ions are the nephrons. The formation of these functional units is referred to as nephrogenesis. Human nephrogenesis (development of kidney nephrons) is completed before birth. The number of nephrons in normal human kidneys ranges from approximately 300,000 to more than one million. After birth, the nephron number is complete and no new nephrons are able to be formed. In humans, development of the permanent kidney begins around gestational week 5. In the third trimester, 60% of nephrons are formed and continue to form until approximately 36 weeks. No new nephrons are formed after this time.
In the mouse (as with humans), there are three embryonic kidneys, the pronephros, mesonephros and metanephros, and the development of the final permanent kidney, the metanephros, begins with the outgrowth of ureteric bud, originating from the Wollfian duct, invading the surrounding metanephric mesenchyme. This occurs at around embryonic day 9-10.5 (E9-10.5) and requires inductive signals from the metanephric mesenchyme to initiate bud development. The induced mesenchyme sends reciprocal signals to induce growth and branching of the ureteric bud. Nephron formation (nephrogenesis) is induced when factors secreted by the ureteric bud cause the induction, condensation and aggregation of the mesenchyme. Each aggregate undergoes epithelialisation and then proceeds through the developmental stages of the polarised vesicle stage, the comma and the S-stage. There is continued branching with new aggregates forming at the tips, and this process continues with the induction of new nephrons. By the end of nephrogenesis, there are more than 26 terminally differentiated cell types with distinct location, morphology and function. Unlike the human, in the mouse kidney development continues in mice until around 7-10 days after birth.
Growth Factors in Kidney and Lung Development:
Growth factors, aside from their influence in cell growth, contribute greatly to many processes including cell migration, morphogenesis, differentiation and proliferation. The roles of growth factors in branching morphogenesis in the lung and nephrogenesis in the kidney are controlled by an array of inductive and inhibitory signals. The crucial roles of factors including insulin-like growth factor-I and II (IGF-I and IGF-II), hepatocyte growth factor (HGF), and epithelial growth factor (EGF) have been well established in the developing lung and kidney. It is, however, considered that there may be numerous other growth factors which play significant roles in development of the lung and kidney.
In has been found that in warm blooded animals, usings the embodiments disclosed it is possible to promote organ development (as reflected in, for some organs, an increase in organ weight), and more particularly, increased growth and/or enhanced nephrogenesis and lung maturation. It has also been found that promoting organ development and/or maturation in a warm blooded premature infant or foetus is possible.